Pharma Lobbyists Have Their Way: FDA “Breakthough-Drug” Policy

A group from the excellent Pharmacoepidemiology-Pharmacoeconomics center at Harvard, a.k.a. Dr. Jerry Avorn and friends, wrote this commentary in the current New England Journal:
http://www.nejm.org/doi/full/10.1056/NEJMhle1311493

If you skip to the very end to see their conclusion: “In the next few years, evidence will accumulate to indicate how well the new breakthrough-therapy designation improves the options of patients with serious and intractable diseases and to what extent it facilitates the market entry of treatments that promise more than they can deliver.”—then you’d guess that they are pretty wishy-washy about the new category of “breakthrough therapy” that Congress enacted in 2012. A close reading shows that you’d be wrong; if you check out all the fine print you’ll see that the authors are very negative about this new FDA category aimed at hastening new drug approval.

Why the negativity? The points they make are:

• There’s really no good evidence that currently, patients suffer as a result of slow FDA approvals. FDA approval times are steadily decreasing.
• There’s some evidence at least that unsafe drugs are getting onto the market because of current FDA approval practices. The authors mention among other examples the leukemia drug, ponatinib, approved on an accelerated basis in 2012, then temporarily suspended in 2013 when it was shown that nearly half of patients on the drug followed for 2.7 years developed serious blood-clotting events like heart attacks and strokes.
• Before Congress enacted this new “breakthrough” category, there were already several pathways for “fast track” approvals.
• In the first year after the “breakthrough” category was approved, the FDA received 92 new drug applications for this designation. As I noted in HOOKED and previously on this blog, in recent years, sober appraisals of new drugs have shown repeatedly that no more than a small percentage of new drugs qualify as significant advances over existing therapies. If this many drugs are seeking approval under the new designation, it is certainly being used for drugs that aren’t “breakthroughs” in any meaningful sense of the term. (The FDA approved only 27 of those applications.)
• We’ve seen many times here how a good way to approve a useless or a harmful drug is to look only at surrogate endpoints and not at meaningful patient outcomes. Under previous rules, a drug had to show activity first against a “well-established surrogate endpoint,” and then later, it was all right to address a “less-than-well-established surrogate endpoint,” whatever that is. Apparently even that was not loosey-goosey enough for Pharma, so this “breakthrough” category allows approval based on “an effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease.” (And here I would have thought that would be the definition for an “acceptable surrogate endpoint”—shows how much I know.)

The bottom line seems to be that the drug industry lobby continues to have its way in Congress and can get most any legislation passed they want. I suppose the next thing is that they will decide that even with this new category, drugs are not being approved fast enough, and so they will come up with a new category that requires that the FDA approve a drug if the company promises (cross its heart and hope to die) that the drug will do something to an almost-acceptable sort-of-surrogate endpoint, sometime in the next 5 years.

When the industry lobbies for a slicker greased pathway through FDA approval, it never comes to Congress by itself; it always comes along with “consumer” lobbyists supposedly representing patients desperate for cures. We’ve also seen numerous times how often those “consumer” groups are actually bankrolled by Pharma, so that pretty much disposes of that argument—but Congress laps it up nonetheless.

I explained in HOOKED how back around 1972, some brilliant Pharma lackey invented the “drug lag,” the claim that people were dying like flies in the U.S. because wonder drugs approved years ago in Europe were being held up by a stodgy, unresponsive FDA. I there compared the “drug lag” to John F. Kennedy’s famous “missile gap.” There are two analogies. One, the “lag” and the “gap” both turned out on investigation to be purely mythical. Two, once given voice, they refused to die, no matter how much proof was amassed on the other side. And so today we still operate under the myth that the FDA is too slow to approve marvelous new wonder drugs and somehow we have to speed up the process. Or at least Congress operates under that myth when huge piles of Pharma lobbying cash are spread around along with it.

Over-Enthusiasm in Research Results: How Pharma Finds a Seam

Every so often I comment on a research study that has nothing directly to do with pharmaceutical matters, but which illustrates some basic points about the medical literature and how apparently authoritative studies can be misleading. As is often the case, I am prompted here by Rick Bukata and Jerry Hoffman in their monthly Primary Care Medical Abstracts. Here I'll rely especially on Jerry's commentary on this paper, utilizing his skills as an evidence-based medicine mayvin.

The paper is:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60852-1/fulltext

The study was funded by NIH and the authors declare no conflicts of interest, so at first blush this would appear to be a poster child for reliable, unbiased research.

The research question is: If you take a group of folks who have had a stroke of one specific type (lacunar strokes, located in the lower portion of the brain and comprising about a quarter of all strokes caused by blood clots), will they do better in the future if you set a lower (less than 130) rather than a higher (130-149) target for controlling their blood pressure? To study this the research group enrolled about 1900 folks at 81 sites in North America, Latin America, and Spain and followed them for nearly 4 years. The local physicians used whatever medicines they wanted to try to reach the blood pressure goals; and the lower-pressure group did in fact achieve a lower blood pressure overall than the higher-target group (11 points difference).

If you listen to the authors of the paper, they'll tell you:

• While none of the results of the study were statistically significant, the so-called "trends" were in the direction of fewer strokes of all sorts, and fewer bad vascular events, in the lower-pressure-target group.
• The lower-pressure target group did not seem to have any more serious side effects from treatment.
• Other previous studies have tended to show benefits from lower blood pressure in similar populations
• Therefore, we should recommend setting the blood pressure targets lower for patients who have had a lacunar stroke.

If on the other hand you listen to Dr. Jerry Hoffman's critique (subscription required), he'll tell you:

• Since no results were statistically significant, that means the study failed to show any real benefit from the lower blood pressure target in these patients.
• Let's for a minute pretend that all the so-called "trends" were in fact statistically significant. We'd still have to ask how large the resulting differences were. It turns out that the differences are really tiny anyway--often in the fractions of a percentage point.
• If you are going to look at slight, nonsignificant trends, how about the slightly higher overall mortality rate in the lower blood pressure target arm of the study? Funny how the authors get so excited about "trends" that confirm their hypothesis, and yet ignore similar "trends" that go the wrong way.

So what's going on here? A large group of enthusiastic and dedicated investigators spent years and tons of NIH money at 81 different sites all over the world. You can't blame them if they were desperate to rescue something of value from  their disappointing numbers. Sadly, that doesn't make it good science.

If good scientists like this can publish results that are so little supported by their data, and a supposedly excellent journal lets them get away with it-- then what happens when to the natural enthusiasm of the research team, we add the incentives as well as the incredible monetary resources of the drug industry? You start to get a sense of how much misleading information can appear on the pages of the "best" medical journals, and how long it could take us to sort through it all and decide what's really best for patients.

Pharma Slashes Budgets for Physician Speakers--Why?

The nice folks over at ProPublica:
http://www.propublica.org/article/as-full-disclosure-nears-doctors-pay-for-drug-talks-plummets
--who gave us their Dollars for Docs web tool to track drug company payments to individual physicians, now report major drops in recently reported expenditures for promotional speakers. For example:

• Eli Lilly, from $47.9M in 2011 to $21.6M in 2012
• Pfizer, $22M in 2011, $8.3M in 2012
• Novartis, $24.8M in 2010-11, $14.8M the following year
• GlaxoSmithKline, $24M in 2011, $9.3M in 2012 (and announced last December it would stop using physicians as paid speakers entirely)

This was not true of all companies; AstraZeneca stayed flat (though they had declined sharply the previous year) and Johnson & Johnson posted a 17% increase. One company only began reporting figures in the past year, Forest Labs, and this relatively small company, interestingly, topped all the giants by spending $40M on physician speakers.

A brief reminder: Dollars for Docs became possible after several drug companies, either voluntarily or as a result of legal settlements for marketing infractions, began to make public their payments to physicians, which ProPublica then kindly gathered into one central location. The Physician Payment Sunshine Act, a part of the Affordable Care Act of 2010, does not kick in till later this year, after which all companies will be required to report.

So--why these steep cuts? One possibility, apparently favored by the ProPublica reporters, is the Sunshine Act looming, and the increasing degree of suspicion attached to payments to physicians from Pharma. But another possibility they outline is simply the dropoff in major drugs protected by patent--and the increasing tendency of the newer generations of brand-name drugs to be highly specialized drugs used by only a small number of docs, such as a new treatment for Hepatitis C. It may take fewer paid speakers to market these newer drugs, or else companies may be finding new ways to market via the Web that bypasses paid speakers altogether.

What about other types of marketing payments? More recently, ProPublica provided us with a clickable graph:
http://projects.propublica.org/graphics/d4d-slopegraph
This graph enables us to track company by company how spending for meals for docs declined by 20%, for "gifts" by 47%, for travel by 29%, and for consulting by 18.7% (among the companies reporting). That raises the interesting question of whether, for the first time in recent history, we may be seeing an actual fall-off in the total amount Pharma spends on marketing--or whether it's the proverbial balloon that if you push in one end it simply bulges out the other. Only just now no one seems clear on where the other end of the balloon might be. As I described in HOOKED, the companies themselves are quite secretive about the actual amounts they spend on marketing.

A Bit of History--Louis Lasagna and the Creation of the Center for the Study of Drug Development

One focus in HOOKED is the need to appreciate the history of the pharmaceutical industry in the 20th century, to trace today's developments to their origins. In a similar historical vein, I've called attention in this blog to the belief system I like to call "economism":
http://brodyhooked.blogspot.com/2011/11/shameless-commerce-division-new-book.html
--though I am increasingly outnumbered by historians and social scientists who prefer the label neoliberalism.

Economism/neoliberalism (E/N) is an ideology generally characterized as faith in the unregulated free market along with demands for tax cuts and corporate-friendly government policies. However, as economist Philip Mirowski (Never Let a Serious Crisis Go to Waste: How Neoliberalism Survived the Financial Meltdown, Verso, 2013) insists, such a description misses one of the key elements of E/N. Originating with Austrian economist Friedrich Hayek, a founder of E/N during the 1940s, is the idea that the market serves not merely as a medium for the exchange of goods and services, but as a perfect information processing system. The price of a commodity in the truly "free" market reflects at any given time the sum of millions of exchanges across the world, and reflects what any commodity is "worth" much more accurately than any alternative way of approaching the problem--such as scientific research, for example. In short, the market is omniscient; in short, the market is God. The fact that no real-life market ever did or ever could function in this manner does not seem to bother any committed believer in E/N--tending to confirm my claim, in The Golden Calf, that E/N pretends to be hard-headed economic science but actually functions logically like a quasi-religion.

By now you are wondering (if you're still awake) what any of this has to do with Pharma. I was moved to address this topic by a recent article (subscription required) by economist Edward Nik-Khah on how a major E/N enterprise, the Chicago School of Economics, played a critical role in the creation of a new E/N think tank, the Center for the Study of Drug Development, initially located at the University of Rochester and later moved to Tufts University. A key figure described by Nik-Khan in this process was the famous clinical pharmacologist, Louis Lasagna (1923-2003).

In his early career Lasagna was a widely respected academic, often credited with originating the field of clinical pharmacology. Like most of his academic fellows he strongly supported the efforts of the FDA to rein in drug-industry advertising and replace misleading marketing with solid science. He was initially a supporter of the Kefauver-Harris amendments of 1962 that strengthened the FDA's regulatory powers. But through the 1970s something changed. Lasagna cast the sole vote on a review committee of the National Academy of Science in favor of Upjohn and its drug Panalba, that the FDA was trying to take off the market as ineffective. Lasagna took his losing case to the public through an editorial in the Wall Street Journal. Eventually he became the co-founder of the CSDD at his home university, Rochester. The CSDD became a supposedly independent unit to study the science and economics of drug development, but was in actuality captive to the drug industry that funded it. Its most notorious product was the estimate of "the $800 Million Pill," the widely-criticized (but also widely believed) figure of how much the industry must spend in research to create a single successful new drug (discussed at length in HOOKED).

Nik-Khah never documents precisely how Lasagna was "turned" from a position in keeping with academic clinical pharmacology to a stance at odds with virtually all his fellow academics. But he does show that Lasagna attended a conference sponsored by the Chicago School of Economics in 1972, organized and attended by such E/N figures as Milton Friedman and George Stigler, which became a one-sided mouthpiece for promulgating E/N doctrine in opposition to government regulation of the drug industry. (One of the key Chicago staffers later argued that weakening drug regulation would still be worth it economically even if it produced several thalidomide tragedies, because of the greater benefits of allowing more wonderful new drugs to reach the market quicker.)

Following Lasagna's attendance at the Chicago conference and his WSJ piece, the chancellor at Rochester, Allen Wallis, who traveled in the highest E/N circles of that day, took Lasagna under his wing and suggested the creation of the CSDD, personally interceding with drug companies and pro-business foundations to fund it. (Following good free market principles, Tufts eventually stole the CSDD away from Rochester by offering more money, in an effort to build its own drug-industry-funding portfolio.)

Nik-Khah illustrated how Lasagna had signed on to the E/N agenda by quoting extensively from some of his later writing on deregulation of the drug industry. Lasagna eventually turned against academic science almost totally. He argued instead that the minimal amount of clinical trial research should be required to get a drug onto the market, and thereafter the company should be responsible for monitoring how the drug performed as to safety. He viewed the ideal state of affairs as the physician and patient being bombarded with information from numerous sources, including industry marketing, and then making up their own minds as to using the drug. The clash of multiple, conflicting information sources would work much better than any scientific study as a way to find out the truth about the drug. If patients complained that they were ill-equipped to sort through such detailed, technical data, Lasagna replied--tough, this is the real world, live with it. In short, Lasagna spoke like a true convert to E/N, believing that the "free market" of ideas was far superior to, and much more reliable than, scientific research.

Another telling quote from Lasagna's writing during this time is what he called the supposed censorship imposed on industry by overweening FDA regulations, according to his view--he deemed it "Lysenkoism," comparing the FDA with the Stalinist suppression of Mendelian genetics in the USSR. Daniel Stedman Jones's political history of E/N (Masters of the Universe: Hayek, Friedman, and the Birth of Neoliberal Politics, Princeton, 2012) points out that the major founders of E/N, Hayek and Friedman, shared a conviction that all "collectivism" was cut from the same cloth, whether it be Hitler's Germany, Stalin's Russia, the New Deal, Britain's welfare state, or even a labor union. A doctrinaire anti-communism all during the Cold War characterized their public utterances. By invoking a Stalinist bogeyman, Lasagna indicated that he was singing straight out of the E/N hymnal.

Nik-Khah's work seems a useful historical exploration of how many of the pro-Pharma policies and politics that emerged in the US in the later decades of the 20th century can be traced directly to the influence of the E/N ideology, and how the echo chamber of E/N institutions helped to spread the word. (Hat tip to my colleague Daniel Goldberg for recommending this article.)

Nik-Khah E. Neoliberal pharmaceutical science and the Chicago School of Economics.  Social Studies of Science, 2014, e-published ahead of print

Addendum 4/13/14: By coincidence, I have recently finished reading Dominique Tobbell's book, Pills, Power, and Policy: The Struggle for Drug Reform in Cold War America and Its Consequences (University of California Press/Millbank Books, 2011). Historian Tobbell paints quite a different picture of how Louis Lasagna did a 180 on the FDA. According to her account, Lasagna's conversion was much more gradual, was based at least in part on a reasoned assessment of how the FDA appeared to be overreaching in its responses to the 1962 post-thalidomide Congressional amendments, and was already largely completed by the time he was first exposed to a strong dose of E/N. So before one buys into Nik-Khah's account, it's only fair to mention this alternative assessment.